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Determining the structure of RNA polmerase II C-terminal domain in complex with ALS-linked FET protein assemblies


Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by the presence of pathological protein aggregates in affected neurons. RNA-binding FET (FUS, EWS, and TAF15) proteins are frequently observed in ALS-linked neuronal aggregates, and mutations in genes encoding FET proteins segregate with disease in familial ALS cases. In functional cells, FET proteins exist in dynamic higher-order assemblies in ribonucleoprotein (RNP) granules, and these granules may serve as nucleation sites for disease aggregates. Here we show that Fused in sarcoma (FUS) forms a droplet state mimicking RNP granules in vitro. Moreover, low levels of RNA stimulate FUS droplet formation, but changes in ionic strength have little effect on droplet formation, suggesting that interactions between FUS molecules are not held together primarily by electrostatic interactions. Separately, we investigated interactions between the RNA polymerase II C-terminal domain (CTD) and assemblies of FET protein transcriptional activation domains. Recent studies have shown that FET protein transcriptional activation domains can assemble into a hydrogel-like state in vitro, and such polymerization is required for both transcriptional activation and CTD binding. Here we present the first atomistic view of the dynamic complex formed between self-assembled FET proteins and the RNA pol II CTD. We report that RNA Pol II CTD binds to droplets formed by the SYGQ-rich low complexity (LC) transcriptional activation domain of FUS. We also show that RNA Pol II CTD binds to hydrogels formed by the low complexity (LC) transcriptional activation domain of TATA-binding protein-associated factor 2N (TAF15) in a residue-specific manner.


Janke, Abigail, "Determining the structure of RNA polmerase II C-terminal domain in complex with ALS-linked FET protein assemblies" (2015). Summer Research Symposium. Brown Digital Repository. Brown University Library.



  • Summer Research Symposium

    Each year, Brown University showcases the research of its undergraduates at the Summer Research Symposium. More than half of the student-researchers are UTRA recipients, while others receive funding from a variety of Brown-administered and national programs and fellowships and go …